NO168355B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE BENZIMIDAZOLD DERIVATIVES - Google Patents

Description

The present invention relates to the production of new benzlmldazole compounds which have therapeutic activity, and more specifically, these compounds are used for the prevention or inhibition of gastric acid secretion.

A number of different benzothiazole-2-sulfinamides are known for use as vulcanization accelerators, for example from US patents 2,585,155 and 3,541,060, FR patents 1,003,821 and 2,037,001, and from DE patent 1,949,615. A number of 2 -(pyridyl-methylsulfinyl)benzimidazoles are known for use as pharmaceuticals, namely from EP patent 5129 and GB patent 2 134 523, and a number of 2-(heterocyclicmethylsulfinyl)benzimidazoles are known from EP patent 1279, CE patent 623 582, DE patent 2 548 340 and FR patent 2 392 021. GB patent 1 271 650 describes 2-(piperidinoalkyl)- and 2-(morpholinoalkyl)sulfinylbenzimidazoles, and GB patent 214 129 describes N-alkanoyl substituted benzimidazoles. Furthermore, SE describes the patent application, publ. No. 8504048.3 2-(phenylalkylsulfinyl)benzimidazoles.

The above-mentioned new benzimidazoles produced according to the present invention have the general formula:

where Rj , R 2 , R 3 , R 4 , R 5 , R f , R 7 , and R 7 , which may be the same or different, are each hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl carbonyl, C 1 -C 6 fluoroalkyl, (alkyl C 1 -C 4 )phenyl-sulfonyl, nitro, amino or carboxy, or a C 1 -C 6 alkyl ester thereof,

in addition, R 2 and R 3 may form the chain -CH-CH-CH-CH-;

R 8 and R 10 , which may be Uke or different, each is hydrogen, alkyl C 1 -C 8 , phenyl or cycloalkyl containing up to 6 carbon atoms; or

Rq and R10 may, together with the nitrogen atom to which they are attached, form a piperldlnyl or morpholinyl ring, or

Rq has the above meaning with the exception that it cannot form a ring with R^n» and Rg and R^q together with the nitrogen atom and the carbon atoms 1 form the ring to which the nitrogen atom and Rg are attached, a 1,2, 3,4-tetrahydroquino-linyl ring,

Y is 0, 1 or 2;

R15 is hydrogen, -C00R or alkyl C1-C8 where the latter is optionally substituted with -ØGOR,

R is hydrogen or alkyl Gj-Gg,;

or a pharmaceutically acceptable salt thereof.

According to the present invention, the compounds of formula I are prepared by

(a) oxidizes a corresponding compound of the formula: where R 1 ( R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 8 , R 15 and y have the above-mentioned meanings, (b) for the preparation of a compound of formula (I) where R 5 has the above-mentioned meaning except that it cannot be hydrogen, reacts a corresponding compound of formula (I) where R15 is hydrogen, with a compound R15Z where Rj5 has the meaning given above, except that it cannot be hydrogen, and Z is a leaving group, or ( c) for the preparation of a compound of formula (I) where R } , R 2 , R 3 , R 4 , R 5 , R g , R 7 and R g are an amino group, reduces a corresponding compound of formula (I) bearing a -NO 2 group,

and, if desired or necessary, converting the resulting compound of formula (I) into a pharmaceutically acceptable salt thereof or vice versa.

The oxidation in method (a) can be carried out in a solvent which is inert under the reaction conditions, for example ethyl acetate, dichloromethane, chloroform or a mixture thereof. The reaction is preferably carried out at below room temperature, for example from -20 to 10°C. Suitable oxidizing agents for use in the reaction are peracids, for example m-chloroperbenzozyre or t-butyl hydroperoxide in the presence of a suitable catalyst, for example venadyl acetylacetonate.

In method (b), the leaving group can for example be halogen and the reaction can be carried out in a solvent which is inert under the reaction conditions, for example dimethylformamide, in the presence of a base and at a temperature of about 15 to 30°C.

In method (c), the reduction can for example be carried out chemically under basic conditions, for example using hydrazine and Raney nickel, but is preferably carried out catalytically, for example using a PtP2 catalyst and ethanol as reaction medium.

The compounds of formula (VI) can be prepared by conventional processes known per se, for example by reacting a compound of the formula

where R 1 , R 2 , R 3 , R 4 and R 15 have the meanings given above with a compound of the formula:

where R5, Rg, R7, Rg» Kg, R10 °fi Y have the meanings given above, and Z is a leaving group, for example halogen (chlorine).

The reaction can be carried out in a suitable solvent, for example N,N-dimethylformamide, and in the presence of an acid acceptor, for example calcium carbonate.

The compounds of formulas (VII) and (VIII) are either known or can be prepared from known compounds using conventional techniques.

The compounds of formula (I) and the intermediates for their preparation can be isolated from their reaction mixtures using conventional techniques.

Pharmaceutically acceptable salts of compounds of formula (I) include salts with suitable organic or inorganic acids, for example with a hydrohalic acid, sulfuric acid, alkanesulfonic acid, tartaric acid or citric acid. When the compound of formula (I) has a -COOH group or another acid group, salts with suitable organic or inorganic bases are also provided, for example ammonium, alkali metal, alkaline earth metal and alkyl amino salts and so on. The benzimidazole ring itself is acidic and can form salts with suitable bases as indicated above.

The compounds of formula (I) and pharmaceutically acceptable salts thereof are useful because they possess pharmacological activity in animals; in particular, they are useful because they prevent or inhibit gastric acid secretion, for example in the test set forth in Am J. Physiol., 1982, 243(6), G505-510. The compounds of formula (I) are also useful as intermediates in the synthesis of other chemicals.

The new compounds are thus indicated for use in preventing or inhibiting gastric acid secretion, and/or treating conditions that normally involve an excess of gastric acid secretion, for example peptic, duodenal, gastric, periodic or stomal ulceration, dyspepsia, duodenitis, Zollinger-Ellison syndrome, reflux oseophagitis and bleeding, for example from erosion of an ulcer in the upper gastrointestinal tract, especially when a major blood vessel is not involved. The compounds can also be used for the treatment of gastritis or dyspepsia associated with the administration of non-steroidal anti-inflammatory drugs, in the prophylaxis of bleeding in the gastrointestinal tract from stress ulceration in seriously ill or burned patients, in the prophylaxis of periodic bleeding in patients with bleeding peptic ulcer, before general anesthesia in patients at risk of acid aspiration syndrome (Mendelson's syndrome) and to reduce the chance of bleeding in patients with leukaemia, transplant versus host disease or with severe hepatic failure. The conditions stated above can be treated whether they are associated with excess gastric acid secretion or not.

Patterns of therapeutic use that can be mentioned are:

a) a high dose initially, for example 2-4 weeks, followed by continued therapy at a lower dose after that

the condition has improved, for example the ulcer is

healed,

b) as in a) above, but continuous therapy including a cytoprotective agent, for example a PGE2 derivative, c) combination therapy using a low dose of the compound of the present invention together with a low,

well tolerated dose of et. cytoprotective agent and/or

anti owned,

d) intermittent dosing, for example every other day, may be appropriate as maintenance therapy.

For the above-mentioned applications, the dose administered will naturally vary with the compound used, the method of administration and the desired treatment. In general, however, satisfactory results are obtained when the compounds are administered at a dosage of from 10~^M to 19~^M in the test indicated in Am. J. Physiol., 1982 243(6), G505-G510. For humans, the indicated total daily dose ranges from 1 to 3000 mg, preferably 5 to 500 mg, and most preferably from 10 to 200 mg, which may be administered in divided doses from 1 to 6 times daily or in a sustained release form. Thus, the unit dosage forms suitable for administration comprise from 1.0 to 600 mg of the compound mixed with a solid or liquid pharmaceutically acceptable diluent, carrier or excipient.

The compounds of formula (I) and pharmaceutically acceptable salts thereof have the advantage that they are more easily absorbed, are less irritating to the gastrointestinal tract, or have less toxic side effects, or are more active, or are more stable against gastric acid when administered by ingestion than compounds of similar structure.

It is preferred that at least one of R 1 , R 2 , R 3 and R 4 , and at least one of R 5 , R 8 , R 7 and R 8 have a meaning other than hydrogen. When R1, R2, R3, R4, R5, Rg, R7 or Rg is halogen, it can be chlorine or fluorine.

It is particularly preferred that each of Rg and Rjq contain 1 or 2 carbon atoms.

Specific groups R 1 to R 4 include hydrogen, phenylcarbonyl, methyl, chlorine, methoxy, CF 3 , NO 2 , p-toluenesulfonyl and

-NH2, and R2 and R3 can form a -CH-CH-CH-CH chain.

It is preferred that y is 0 or 1.

Specific groups R 5 to R 8 include hydrogen, methyl, chlorine, propyl, methoxy and butyl.

Special groups R15 are -COCH3, CH20CO-(t.butyl), -CO2Et and methyl.

Preferred compounds produced according to the invention are:

where Ria, <R>2a» ^5a» °S R6a» which may be the same or different, each is hydrogen, halogen, alkoxy C1-C8 or alkyl C1-C8. R 3 , and R 4 , which may be the same or different, are each hydrogen or alkyl C 1 -C 8 .

Particularly preferred compounds of formula (I) which have beneficial therapeutic activity are N,N-dimethyl-2-(1H-benzlmidazol-2-ylsulfonylmethyl)-benzenamine, N,N-dimethyl-2-(5,6-dimethoxy-1H -benzimIdazol-2-ylsulfinylmethyl)-benzenamine, 2-[1methyl-(1H-2-benzimidazolylsulfinylmethyl)]-N,M-dimethyl-benzenamine and 2-(5-amino-1H-2-benzlmidazolylsulfinylmethyl)-N,N- dimethylbenzenamine.

Some of the compounds with formula (VI) are new and of particular interest are compounds with formula (I) where y is greater than 0.

Pharmaceutical preparations comprise (preferably a smaller proportion) a compound of formula (I) or a pharmaceutically acceptable salt thereof, as active ingredient, 1 mixture with a pharmaceutically acceptable aid, diluent or carrier. Examples of suitable aids, diluents or carriers are: - for tablets and dragees; lactose, starch, talc or stearic acid; for capsules, tartaric or lactose; for suppositories, natural or hardened oils or waxes; and for injections (i.m. or i.v.) or intestinal lavage, surfactants and preservatives. The compounds can also be administered transdermally, for example in an ointment base. Compounds of formula (I) or the pharmaceutically acceptable salt thereof preferably have a mass average diameter of from 0.01 to 10 µm. The compound with a particle size equal to 6 can be produced by grinding or grinding followed, if necessary, by particle size classification, for example using a sieve. The preparations may also contain suitable preserving, stabilizing and wetting agents, solubilizing agents, sweetening, coloring and flavoring agents. If desired, the preparations can be formulated in a form with extended release.

The compounds can, if desired, be administered together with (for example as a mixture with) an antacid buffer.

Preparations that are intended for ingestion by swallowing or rectally and release their contents in the intestine are preferred. Preparations which will pass unaffected through the acidic parts of the gastrointestinal tract are particularly preferred, for example enteric-coated formulations.

The compounds of formula (I) are optically active and can be resolved or separated into their optical isomers using conventional techniques. The invention therefore provides the compounds as their optical isomers, or as mixtures, for example racemic mixtures thereof.

The invention is illustrated by the following examples.

EXAMPLE 1

N. N-Dimethyl-2-(1H-benzimidazol-2-ylsulfinylmethyl)-benzenamine

a) N. N- dimethyl- 2-(1H- benzoimidazol- 2- ylthiomethyl)- benzene- amln

2-Dimethylaminobenzyl chloride hydrochloride (8.18 g) was dissolved in

dry dimethylformamide (100 mL), treated with 2-mercaptobenzimidazole (5.4 g) and anhydrous potassium carbonate (11.0 g) and the resulting mixture stirred at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate, which was washed with water and dried over magnesium sulfate. The solvent was evaporated and the residue recrystallized from toluene to give 5.68 g of a cream colored solid. The product was eluted through a flame chromatograph1 column with dichloromethane/ethyl acetate (9:1) as eluent to obtain a colorless solid, m.p. 158-160°C.

Elemental analysis for C16<H>17<N>3S

Found: C 68.05; H, 609; N, 15.1; S 11,34

Calculated: C, 67.8; H, 6.01; N 14.85; S 11.31 <<>t>.

b) N.N-dlmethyl-2-(1H-benzimldazol-2-vsulfinylmethyl)-benzenamln 98<f>m-chloroperbenzoic acid (0.67 g) was added portionwise over a few minutes to a stirred solution of the product from step a) (1.0 g) in dichloromethane (30 ml) at 0'C. The reaction mixture was stirred for 0.5 h, washed with aqueous saturated sodium bicarbonate solution, then brine and dried. The solvent was evaporated and the residue eluted through a flame chromatography column using dichloromethane/ethyl acetate (7:3) as eluent to obtain 0.6 g of colorless solid, m.p. 120-121'Q.

EXAMPLE 2

By the method described in example 1 and using appropriate starting materials, the following compounds can be prepared: a) i) N,N-dimethyl-2-(5,6-dimethyl-1H-2-benzimidazolyl-thiomethyl)benzeneamln, m.p. 144-146<*>C. 11) N,N-dimethyl-2-(5,6-dlmethyl-1H-2-benzimidazolyl-sulfinylmethyl)benzenamine, m.p. 141-142'C. b) i) 2-(1H-2-benzimldazolylthiomethyl)-N,N,4-trimethyl-benzenamln, m.p. 159-161'C. 11) 2-(1H-2-benzlmidazolyl sulfinylmethyl)-N,N,4-trimethyl-benzeneamln, m.p. 133-134<*>C. c) 1) 2-(1H-2-benzimidazolylthiomethyl)-4-chloro-N,N-dimethyl-benzenamln, m.p. 148-151'C. li) 2-(1H-benzimidazolylsulfinylmethyl)-4-chloro-N,N-dimethyl-benzenamine, m.p. 148-151<*>C. d) i) 2-(5-chloro-1H-2-benzimidazolylthiomethyl)-N,N-dimethyl-benzenamine, m.p. 49-52<*>C. ii) 2-(5-chloro-1H-benzimidazolylsulfinylmethyl)-N,N-dimethyl-benzenamln, m.p. 121-123'C. e) i) 2-(5,6-dichloro-1H-2-benzimidazolylthiomethyl)-N,N-dimethyl-benzenamine, m.p. 128-130'C. i i) 2-(5,6-dichloro-1H-2-benzimidazolylsulfinylmethyl)-N,N-dimethyl-benzenamln, m.p. 147-149<*>C. f) i) Methyl 2-(2-dimethylaminophenylmethylthio)-1H-benzimidazole-4-carboxylate, m.p. 127-129<*>C. ii) Methyl 2-(2-dimethylaminophenylmethylthio)-1H-benzimidazole-5-carboxylate, m.p. 130<*>C (decomp.). g) i) N,N-dimethyl-2-(5-methyl-1H-2-benzimidazolyltolomethyl)-benzeneamln, m.p. 141-143'C. i i ) N,N-dimethyl-2-(5-methyl-1H-2-benzimidazolylsulfinyl-methyl)benzenamine, m.p. 50-52°C. h) 1) 2-[2-(1-piperidyl)phenylmethylthio]-1H-benzimidazole, m.p. 171-172'C.

ii) 2-[2-(1-piperidyl)-phenylmethylsulfinyl]-1H-benzimidazole, m.p. 160-161'C.

i) i) 2-(1H-benzimidazolyl thiomethyl)-N,N-diethylbenzenamine, m.p. 127-128'C.

ii) 2-(1H-2-benzimidazolylsulfinylmethyl)-N,N-diethyl 1-benzeneamln, m.p. 109'C.

J) i) 2-[2-(5-Methoxy-1H-benzimidazolyl)thiomethyl]-N,N-dimethyl-benzenamine. MS: M<+>329.

i i ) 2-[2-(5-Methoxy-1H-benzimidazolyl)sulfinylmethyl)-N,N-dimethyl-benzenamine.

Found: C 60.36%, H 5.81%, N 11.89%, S 9.69%

C17<H>19N302S 1/7 CH2C12

Calculated: C £60.30, H 5.65%, N 12.30%, S 9.38%.

k) i) 2-(5-trifluoromethyl-1H-2-benzimidazolylthiomethyl)-N,N-dimethyl-benzenamine, m.p. 50-51'C.

ii ) 2-(5-trifluoromethyl-1H-2-benzimidazolylthiomethyl)-N,N-dimethyl-benzenamine, m.p. 50-51'C. 1) i) N,N-dimethyl-2-(5-nitro-1H-2-benzimidazolylthiomethyl)-benzeneamln, m.p. 146-148°C.

ii ) N,N-dimethyl-2-(5-nitro-1H2-benzimidazolylsulfinyl-methyl)-benzenamine, m.p. 105-106°C (d).

m) i) [2-(2-N,N-dimethylaminophenylmethylthio)-1H-5-benz-imidazolyl]phenylmethanone, m.p. 62°C.

i i ) [2 - ( 2-N ,N-di ime ty lam in of eny Ime tyl sulf f inyl )-1H-5-benzimidazolyl]phenylmethanone, m.p. 74<*>C.

n) i) 2-(5,6-dimethoxy-1H-2-benzimidazolylthiomethyl)-N,N-dimethyl-benzenamine, m.p. 93-95<*>C.

11) 2 - (5, 6-dimethoxy-1H-2-benzlmidazolylsulfinylmethyl)-N,N-dlmethyl-benzenamln, m.p. 142-144<*>C.

o) i) N,N-dimethyl-2-(4-trifluoromethyl-1H-2-benzimidazolyl-thiomethyl)-benzenamine, m.p. 93-95<*>C.

i i ) N ,N-dlmethyl-2-(4-trifluoromethyl-1H-2-benzimidazolyl-6ulfinylmethyl)-benzenamine, m.p. 129-130'C.

p) i) N,N-dimethyl-2-(1H-2-naphtho[2,3-d]imidazolylthiomethyl)-benzenamine, m.p. 178°C (d).

i i ) N,N-dimethyl -2-(1H-2-naphtho[2,3-d]imidazolylsulfinyl-methyl)-benzenamine, m.p. 129<*>C (d).

q) 2-(2-(1H-benzimidazolyl)sylphenyl)-benzenamine, m.p. 202-203°C, shrinks at 160°C.

EXAMPLE 3

2- ( lH- 2- benz imidazol yl sul f ln vime tvi ) - N. N- dimethyl- 6- propyl-benzenamln.

a) 2-methoxy-3-propylbenzoic acid

Methyl 2-methoxy-3-propylbenzoate (1.9 g) was dissolved in methanol

(300ml). Sodium hydroxy (16.6 g) in water (100 ml) was added and the mixture was heated under reflux for 3 hours. The solvent was evaporated and the mixture acidified with dilute hydrochloric acid. The product was extracted with ethyl acetate (800 ml), washed with water, dried over magnesium sulfate and the solvent evaporated. Extraction of the resulting brown oil with hot pentane gave 25.9 g of the subtitle compound as a yellow solid, m.p. 55-58°C.

b ) JJ - ( 1 . l- dlroet. vI- 2- hydroxyvetyl ) - 2 - me t ox v- 3 - propyl - benzenamide

2-Methoxy-3-propylbenzoic acid (25.3 g) in dry dichloromethane (400 mL) was heated at reflux with thlonyl chloride (17 mL) for 3 h and then stirred at room temperature for 14 h. The solvent was evaporated and the product distilled using a Kugelruhr apparatus (air bath temperature 135°C; 0.35 mmHg)) to give 24.1 g of a pale yellow oil. This oil was dissolved in dry dichloromethane (200 ml) and added gradually to a stirred solution of 2-amino-2-methylpropanol (20.2 g) in dichloromethane (200 ml) at below 0<*>C under N2 • The reaction mixture was heated at room temperature for 18 hours. The product was extracted with chloroform (300 ml) and washed with dilute hydrochloric acid (150 ml), sodium carbonate solution (150 ml) and brine (100 ml) and then dried over magnesium sulfate. After evaporation of the solvent, the subtitle compound was crystallized from cyclohexane as a white solid (20.4 g), m.p. 95-96.5<*>C.

c) 4. 5- dihydro- 2- methoxy- 3- propylphenyl- 4. 4- dimethyl- oxazole

The product from step b) (20.4 g) was stirred in dry dichloromethane

(200 ml) and cooled to 0°C. Thlonyl chloride (17 mL) was added and the reaction mixture was stirred at room temperature for 2 hours. The solvent and thlonyl chloride were evaporated and the residue was treated with ether. Water was added to the solid and the mixture was basified with dilute sodium hydroxide solution. The product was extracted with ether (500 mL), washed with brine (150 mL) and dried over magnesium sulfate. The solvent was then evaporated and the product purified by flame chromatography using 10% ethyl acetate/90% petroleum ether as its eluent, and by distillation using a Kugelruhr apparatus (air bath temperature 135<*>C; 0.7 mmHg) to obtain the compound in subtitle (17 g) as a colorless oil.

d) 2-(4.5-Dihydro-4.H-Dimethyl-oxazol-2-yl)-N.N-Dimethyl-6-propyl-benzenemln

Dimethylamine (9 mL) was added to dry tetrahydrofuran (120 mL) and the mixture cooled to -15°C and stirred under N 2 with addition of n-butyllithium solution (81 mL, 1.6 M in hexane). The reaction mixture was stirred at -16°C for 40 minutes. The product from step c) (16 g) in dry tetrahydrofuran (100 ml) was added and the mixture was allowed to warm to room temperature and was then stirred for 20 hours. The reaction mixture was quenched with water and the product extracted with ethyl acetate (500 ml), washed with brine (100 ml) and dried over magnesium sulfate. The solvent was evaporated and the product distilled using a Kugelruhr apparatus (air bath temperature 135°C; 0.25 mmHg) to afford 16.4 g of the subtitle compound as a pale yellow oil.

e) 2-dimethylamino-3-propylbenzenemethanol

The product from step d) (17.3 g) was heated at reflux

in 2M dilute hydrochloric acid (480 ml) 1 20 hours. The solvent was evaporated and the residue dried over phosphorus pentoxide. This product was then dissolved in dry tetrahydrofuran (500 mL), cooled in ice and stirred under N 2 with the addition of borane-tetrahydrofuran (300 mL of 1M in tetrahydrofuran). The reaction mixture was stirred at room temperature for 68 hours and was then quenched with methanol. The solvent was evaporated and the product extracted with ethyl acetate, washed with sodium bicarbonate solution (150 ml) and with brine (150 ml) and dried over magnesium sulfate. The solvent was evaporated and the product distilled using a Kugelruhr apparatus (air bath temperature 156<*>C; 1.0 mmHg) to afford the subtitle compound (13.2 g) as a pale yellow oil.

f) 2- chloromethyl- 6- propyl- N. N- dimethylbenzenamine- hydrochloride

The product from step e) 13.1 g) was cooled to 0°C in dry

dichloromethane (50 mL) and stirred while adding thlonyl chloride (6 mL). The mixture was heated at reflux for 1.5 hours. The solvent was evaporated and ethereal HCl was added. The product was collected and then triturated with dry ether to give 6.8 g of the subtitle product as a cream solid.

g) 2-( 1H- 2- benzimidazolvltlomethvl )- N. N- dlmethyl- 6- propyl-benzenamln

The product in step f) was converted to the compound in the subtitle (m.p. 147-150°C) by the method in example la.

h ) 2-(1H-2-benzimidazolylsulfinylmethyl)-N.N-dimethyl-6-propyl-benzeneamln

The product in step g) was converted to the title compound (m.p. 145-147.5°C) by the method in example 1b.

EXAMPLE 4

By the method described in example 3 and using suitable starting materials, the following compounds can be prepared: a) i) 2-(1H-2-benzimidazolylthiomethyl)-4-methoxy-N,N-dimethyl-benzenamine, m.p. 144-145'C. ii) 2-(1H-2-benzimidazolylsulfinylmethyl)-4-methoxy-N,N-dimethyl-benzenamine, mp 130-131°C. b) i) 2-(1H-2-benzimidazolyltolomethyl)-N-ethyl-N-propyl-benzeneamln, m.p. 121°C. ii ) 2-(1H-2-benzimidazolylsulfinylmethyl)-N-ethyl-N-propyl-benzenamine, m.p. 114°C. c) i) 2-[2-( 4-morphol inyl )phenylmethyl thio]-1H-benzeneimidazole, m.p. 170"C.

ii) 2-[2-(4-morpholinyl)phenylmethylsulfinyl]-1H-benzeneimidazole, m.p. 74-76°C.

EXAMPLE 5

2-(1.2.3.4-tetrahydro-1.6-dimethylconolin-8-ylmethylsulfinyl)-1H-benzimldazole

a) 1. 2. 3. 4- tetrahydro- 6- methylquinolln

6-methylquinoline (5.16 g; 36 mmol) and pyridyl/borane complex

(13.2 mL; 144 mmol) in acetic acid (75 mL) was stirred at room temperature for 18 h. The product mixture was treated with dilute aqueous HCl (30 mL) with stirring then basified (40% NaOH, then NaHCO 3 to pH 8) and extracted with ethyl acetate (3x). The combined organic extracts were washed with water (3 times), dried (NagSO4) and evaporated to give a brown oil which was flame chromatographed. Petroleum ether (bp. 40-60°C)/ether (3/1) gave the subtitle compound as a low-melting solid (4.7 g 67%); m/e 147 (base peak).

b) 1. 2. 3. 4- tetrahydro- 1. 6- dimethylquinoline

6-Methyltetrahydroquinoline (3.8 g; 25.8 mmol) in dry methylene chloride (75 mL) was treated with trimethyloxonium fluoroborate (5.2 g; 2.5 mmol) and stirred at room temperature for 20 h. The mixture was poured into saturated aqueous sodium hydrogencarbonate and the organic completely removed. The aqueous layer was extracted with CHCl 2 (2 times). The combined organic extracts were washed with water (2x), dried (Na 2 SO 4 ) and evaporated to give a yellow oil which was flame chromatographed. Petroleum ether (bp. 40-60°C )/ether (5/1) eluted the subtitle compound as a pale yellow oil.

m/z 161 (MW - base peak), 160, 146, 145, 144, 131, 117, 91, 77. c) 1. 2. 3. 4- tetrahydro- 1. 6- dlmethylquinoline- 8- carboxaldehyde Phosphoryl chloride (1 .17 ml; 1.982 g; 12.5 mmol) was added dropwise to a solution of the product in step b) (2.1 g; 10.3 mmol) in dry dimethylformamide (7 ml) under N 2 in an ice bath with stirring. The reaction mixture was heated to 120°C (instantaneous) and then held at 80°C for 2 hours. The mixture was cooled, poured into dilute aqueous NaHCO 3 and extracted with ethyl acetate (3 times). The combined organic extracts were washed with water (3x), dried (NaSO4 ) and evaporated to afford the sub-title compound as a yellow oil, 960 mg (49*). m/z 189 (MW - base peak), 172, 160, 144, 132, 117, 105, 91.

'HNMR (CDCl 3 ) aldehyde at δ 10.06.

d) 1. 2. 3. 4- tetrahydro- 8- hydroxymethyl- 1. 6- dlmethylquinoline

Sodium borohydride (300 mg; 7.94 mmol) was added portionwise

to the product from step c) (1.5 g; 7.94 mmol) in ethanol with stirring at room temperature over 10 minutes. The mixture was stirred for an additional 20 minutes, poured into water and extracted with ethyl acetate (3 times). The combined organic extracts were washed with water (2x), dried (NagSO4) and evaporated to afford the sub-title compound as a viscous pale yellow oil (1.41 g (93%).

m/z (mono TMS derivative) 263 (MW), 248 (base peak) 172, 73.

e ) 1 . 2. 3. 4-tetrahydro-8-chloromethyl-1. 6-Dimethyl-Chloroline Hydrochloride

The product from step d) (1.4 g; 7.33 mol) in dry benzene (10 mL) was treated portionwise with thlonyl chloride (0.8 mL; 1.31 g; 11 mmol) in a cold water bath with stirring. The mixture was allowed to warm to room temperature (2 hours) and then heated at 50° C. (1 hour). It was then cooled again and treated with ethereal HCl (2 mL) and evaporated to dryness. The resulting brown solid was triturated with ether and filtered off to afford the subtitle compound 1 as a light brown solid, 1.73 g (96%). m/z 209/11 (MW), 174 (base peak), 158, 145, 131, 119, 91.

f.) 2-( 1. 2. 3. 4- tetrahydro- 1. 6- dimethyl- quinol- 8- ylmethyl-sulfInyl)- 1H- benzimidazole

The product from step e) was converted to the compound in the subtitle (m.p. 85-88°C, d) by the method in example la.

g) 2-(1.2.3.4-tetrahydro-1.6-dlmethylchloroquinol-8-ylmethyl-sulfinyl)-1H- benzimidazole

The product from step f) was converted into the title compound (m.p. 112-113°C) by the method in example 1b.

EXAMPLE 6

By the method described in example 5, and by using appropriate starting materials, the following compounds can be prepared: a) 1) 2-(1H-2-benzimidazolylthiomethyl)-N,N,3,4,5-pentamethyl-benzenamine, m.p. 161.5-162.5<*>C. ii ) 2-(1H-2-benzimidazolylsulfinylmethyl)-N,N,3,4,5-penta-methyl-benzenamine, m.p. 122-123°C b) i) 2-(1H-2-benzimidazolyl thiomethyl)-4,-methoxy-N,N,3,5-tetramethyl-benzeneamln, m.p. 157-158°C. ii) 2-(1H-2-benzimidazolylsulfinylmethyl)-4-methoxy-N,N,3,5-tetramethyl-benzenamine, m.p. 138-139°C. c) i) 2-(1H-2-benzimidazolyl thiomethyl)-N,N-dimethyl-4-(1,1-dimethylethyl)-benzenamine, m.p. 166-167'C. 11) 2-(1H-2-benzeneimidazolylsulfinylmethyl)-N,N-dlmethyl-4-(1,1-dimethylethyl)-benzenamine, m.p. 130'C.

EXAMPLE 7

2-1"1-(2-Dimethylaminophenyl)ethylsulfinyl-1H-benzimldazole

a) 1-(2-dlmethylaminophenyl)-ethanol

A Grignard reagent was prepared from 2-bromo-N,N-dimethyl-anllin (10.0 g) and magnesium (1.4 g) in dry ether (60 ml) with iodine (1 crystal). The reagent was cooled to 0°C and stirred under a nitrogen atmosphere. A solution of acetaldehyde (3.34 mL) in dry ether (20 mL) was added dropwise over 30 minutes. After stirring at 0°C for 1 hour, the mixture was allowed to warm to room temperature. After a further 2 hours, an aqueous solution of ammonium acetate was added. After 10 minutes, the teams had the opportunity to separate. The aqueous layer was extracted with ether and the combined ether extracts were washed with water and brine then dried and evaporated to give a dark yellow oil, 7.5 g. Flame chromatography (1:1 ether/petroleum ether) gave the desired product as a clear yellow oil, 3.7 g. NMR (CDCl3) S 7.2m(4H), 6.8bd(1H), 5.12q(1H), 2.73S(6H), 1.55d( 3H).

b) 2- ri-(2- dimethylaminopheniyl)ethylthiol- 1H- benzlimidazole

A solution of 2-(2-dimethylaminophenyl)-ethanol (3.6 g) i

dry benzene (50 ml) was cooled in an ice bath and thlonyl chloride (1.17 ml) was added dropwise. After stirring for 1 hour, the mixture was warmed to room temperature and stirring continued for 2 hours. The mixture was concentrated in vacuo and azeotroped with benzene. The residue was taken up in dry dimethylformamide (50 mL) and stirred. To this solution was added a solution of 2-mercaptobenzimldazole (3.22 g) in dry dimethylformamide (30 ml), followed by potassium carbonate (7.5

g). The mixture was stirred at room temperature for 18 hours and then poured onto water containing salt solution, and

extracted with ethyl acetate. The combined extracts were washed with water and brine then dried and evaporated to give a light brown solid, 6.1 g.

Flame chromatography gave the product as a tan solid, 3.4 g.

NMR (CDCl 3 ) S 7.0-7.7m(8H) 5.22q(1H) 2.95S(6H) 1.08d(3H).

c) 2-1"1-(2-Dimethylaminophenyl)-ethyl sulfinyl"! - 1H- benzlmldazole

A solution of the product from step b) (3 g) in ethyl acetate (350 ml) was cooled to -20°C and a solution of metachloroperbenzoic acid (1.83 g) in ethyl acetate (50 ml) was added. After stirring for 1 hour, the mixture was concentrated in vacuo. The resulting gum was dissolved in a minium of dichloromethane and applied to a flame chromatography column. Elution with 1:1 ether/petroleum ether recovered starting material 1.5 g plus both diastereomers of the title compound: Least polar diastereomer 437 mg, m.p. 119-120°C. Most polar diastereomer 298 mg, m.p. 103-105°C.

EXAMPLE 8

[ 2 -( 2- dimethylaminophenylmethylsulfinyl)- 1H- benzimidazol- 1- yl)-methyl- 2- 2- dlmethylpropanoate

A solution of 2-(1H-2-benzimidazolylsulfinylmethyl)-N,N-dimethylbenzamine (1.5 g 5mM) and chloromethyl pivalate (1 ml, 6.9mM) in dry dimethylformamide (20 ml) containing anhydrous potassium carbonate (1.4 g 10.0mM) was stirred at 25°C for 16 hours. The mixture was quenched with water (50 mL) and extracted with ethyl acetate (3 x 100 mL). The organic phase was washed with brine (2 x 25 mL), dried over magnesium sulfate, filtered and evaporated to give a yellow oil which was purified by flash chromatography and eluting with dichloromethane/ethyl acetate (5:1). The desired fractions were evaporated and this gave a yellow oil which solidified on standing. The solid was triturated with pentane, filtered and dried under vacuum (1.2

g); m.p. 70-71'C.

In the same way, the following was produced:

1. Ethyl 2-(2-dimethylaminophenylmethylsulfinyl)-1H-1-benzimidazole carboxylate hemihydrate, m.p. 75-77°C. 2. 2-[1-methyl-( 1H-2-benzimidazolulsulfinylmethyl )]-N,N-dimethylbenzenamine, ms: m/e 313.

EXAMPLE 9

N. N- dimethyl-2- r5-(4-methylphenylsulfonyl)-1H- 2- benzimidazolul-sulfinylmethyl"!-benzenemln

a) 5-(4-methylphenylsulfonyl)-1H-benzlimidazol-2(3H)-thione

4-toluenesulfonylbenzene-1,2-diamln (2.6 g) was dissolved in

dimethylformamide (50 ml) and treated at 60°C with carbon disulfide (6 ml) under nitrogen for 18 hours. The cooled solution was poured into ice water and this gave a yellow precipitate of the sub-title compound, mp 200°C.

b) N.N- dimethyl -2- f5-(4- methylphenylsulfonyl)- 1H- 2- benzlmidazo-1yl thiornetylbenzenamln

The product from step a) was converted to the compound in the subtitle (m.p. 81°C) by the method in example la.

c ) N , N-dimethyl-2-f 5-(4-methylphenylsulfonyl)-1H-2- benzimidazol-ylthionetylbenzenamln

The product from step b) was converted to the title compound (m.p. 85°C) by the method in example 1b.

EXAMPLE 10

By a method similar to that in example 9, the following compounds were prepared: a) i) 2-(4,7-dimethoxy-1H-2-benzimidazolylthiomethyl)-N,N-dimethyl-benzenamine, m.p. 142-144'C.

ii) 2-(4,7-dimethoxy-1H-2-benzimidazolylsulfinylmethyl)-N,N-dimethylbenzenamine, m.p. 61<*>C.

EXAMPLE 11

2-(1H-2benzimidazolvsulfinylmethyl)benzenamine

a) N-(2- hydroxymethylphenyl)-2. 4. 6- triethylbenzenesulfonamld

A solution of (2-[(2,4,6-trimethylphenyl)sulfonyl]-amine)-benzoic acid (5.0 g) in dry tetrahydrofuran (80 mL) was stirred in an ice bath under nitrogen and treated with diborane-tetrahydrofuran- complex (17.3 mL, 1 molar solution) added and stirring continued at room temperature overnight. The reaction mixture was stirred for 3 hours at room temperature, cooled to 0°C and more diborane-tetrahydrofuran complex (17.3 ml, 1 molar solution) added and stirring continued at room temperature overnight. The reaction mixture was again cooled to 0<*>C, more diborane-tetrahydrofuran complex (17.3 mL, 1 molar solution) added and stirring continued at room temperature for 3 hours. Dilute hydrochloric acid was added continuously and the mixture diluted with water and extracted with ethyl acetate, after which it was washed with water and dried over magnesium sulfate. The solvent was evaporated to give 4.0 g of the desired product as an oil. The structure was confirmed by NMR and ms.

b ) N- (2-chloromethylphenyl)-2.4.6-trimethylbenzenesulfonamide

The product of step a) (4.0 g) 1 dry dichloroethane (80 ml) was treated with thlonyl chloride (1.15 ml) at room temperature with stirring. The reaction mixture was stirred for 5 hours, more thlonyl chloride (0.1 mL) was added and stirring was continued overnight. The reaction mixture was then poured into water and the organic layer separated. The aqueous layer was washed with dichloromethane and the organic solutions combined, dried over magnesium sulfate and the solvent evaporated to give 4.06 g of the subtitle compound as a pale yellow oil.

c) N-f 2-(1H-Benzylmazolylthioneretvi)phenyl-2.4.6-1rimethyl-1-phenylsulfonamide

The product of step b) (4.06 g) and 1,3-dihydro-2H-benzimidazol-2-thione (1.9 g) were stirred with anhydrous potassium carbonate (2.1 g) in dry dimethylformamide (70 ml) in 3 hours. The reaction mixture was poured into water and the precipitated product collected by filtration, washed well with water and dried to give 4.39 g of the desired product as a tan powder, m.p. 202-203'C.

d) 2-(1H-2-benzimlazolvlthiomethvlIbenzenamine

The product of step c) (3.87 g) and anisole (4.83 ml) were

treated at room temperature with methanesulfonic acid (29 mL) with stirring. The deep red reaction mixture was stirred for 27 hours very slowly in an excess of aqueous sodium bicarbonate solution and extracted with ethyl acetate, which was then washed with brine and dried. The solvent was evaporated and the residue eluted through a flame chromatograph1 column using dichloromethane/ethyl acetate (4:1) as eluent to give 1.43 g of the desired product as a light brown solid, m.p. 270<e>C (melts at 139“C and solidifies again).

e) 2-(1H-2-benzimidazolylsulfinylmethyl)benzenemln

The product from step d) was oxidized in the same way as i

example 1b to obtain, after recrystallization from ethanol, the title compound as a fluffy, colorless solid, m.p. 177°C (d).

EXAMPLE 12

2 - ( 5- amino- 1H- 2- benzlmidazolylsufinylmethyl)- N. N- dlmethyl-benzenamln

N,N-Dimethyl-2-(5-nitro-1H-2-benzimidazolylsulfinylmethyl)-benzenemln (2.2 g) was hydrogenated 1 ethanol (150 ml) The contents PtOg (0.4 g) under a pressure of 1 atmosphere 1 24 hours. The catalyst was removed and the solvent evaporated in vacuo. The residue was chromatographed (S102/1:10 methanol-ethyl acetate) to obtain the title compound, m.p. 156-157°C (d).

EXAMPLE 13

2-( 1H- 2- benzimldazolyl sulfinylmethyl )- N- cyclohexyl- N- methylbenzenamine

a) 2-(N-cyclohexyl-N-methylamino)benzaldehyde

o-fluorobenzaldehyde (8.68 g) and N-methylcyclohexylamine (11.9

g) was heated under reflux in dimethylformamide (70 ml) containing potassium carbonate (14.49 g) with stirring for 5.5

hours. The cooled reaction mixture was poured into dilute HCl and extracted into CHCl 3 . The aqueous layer was separated and basified with potassium carbonate and extracted into CHCl 3 , which was then washed with water, dried and evaporated to give the sub-title compound (11.8 g).

MS:M<+>217 BP 174.

b) 2-(N-cyclohexyl-N-methylamino)benzene-methanol

The product from step a) was reduced by the method in example 5d

for obtaining the connection in the subtitle.

MS:M<+>219 BP 148.

c) 2-( 1H- 2- benzimldazoIyltlomethvl 1- N- cyclohexyl- N- metvl-benzenamlnd

The product from step b) was converted to the compound in the subtitle by the method in example 5. M.p. 165-166'C.

d) 2 - (lH- 2- benzimidazole, yl sulphnylmethyl1- N- cyclohexyl- N-methyl- benzeneamln

The product from step c) was converted to the title compound by the method in example 1b, m.p. 132-133°C.

Claims (5)

1. Analogous process for the preparation of therapeutically active benzimidazole compounds of the formula: wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 8 , R 7 , and R 8 , which may be the same or different, are each hydrogen, halogen, C 1 -C 8 alkoxy, C 1 -C 8 alkyl, C 1 -C 8 alkyl, phenylcarbonyl, C 1 -C 8 fluoroalkyl, (alkyl C 1 -C 8 -C 8 )phenyl-sulfonyl, nitro, amino or carboxy, or a C 8 -C 8 alkyl ester thereof, in addition, R 2 and R 3 may form the chain -CH=CH-CH=CH-; R q and R i o , which may be the same or different, are each hydrogen, alkyl C 1 -C 8 , phenyl or cycloalkyl containing up to 6 carbon atoms; or Rq and Rig may, together with the nitrogen atom to which they are attached, form a piperidinyl or morpholinyl ring, or R9 has the meaning given above with the exception that it cannot form a ring with R10 and R8°6 ^10 forms, together with the nitrogen atom and the carbon atoms in the ring to which the nitrogen atom and Rg are attached, a 1,2,3, 4-tetra-hydroquino-linyl rlng, Y is 0, 1 or 2; R15 is hydrogen, -COOR or alkyl C1-C8 where the latter is optionally substituted with -OCOR, R is hydrogen or alkyl C 1 -C 8 ; or a pharmaceutically acceptable salt thereof. characterized by: (a) oxidizing a corresponding compound with the formula: where Rlt R2, <R>3, <R>4, <R>5, R6, R7, R8, Rg, R15 and y have the above-mentioned meanings, (b) for the preparation of a compound of formula (I) where R 15 has the above meaning except that it cannot be hydrogen, reacts a corresponding compound of formula (I) where R 5 is hydrogen, with a compound R 15 Z where R 15 has the above meaning except that it cannot be hydrogen, and Z is a leaving group, or (c) for the preparation of a compound of formula (I) where Rj, R2, R3, R4, R5, Rg, R7 and Rg is an amino group, reduces a corresponding compound of formula (I) which carries a -N02 group, and, if desired or necessary, converting the resulting compound of formula (I) into a pharmaceutically acceptable salt thereof or vice versa. 2. Analogous method according to claim 1, for the production of N,N-dimethyl-2-(1H-benz imldazol-2-yl sulfinylmethyl)-benzeneamln, characterized by using correspondingly substituted starting materials. 3. Analogous method according to claim 1, for the production of N,N-dimethyl-2-(5,6-dimethoxy-1H-benzimidazol-2-ylsulfinylmethyl)-benzeneamln, characterized in that correspondingly substituted starting materials are used. 4. Analogous process according to claim 1, for the production of 2-[1-methyl - (1H-2-benzimidazolylsulfinylmethyl)]-n-dimethylbenzene-amine, characterized in that correspondingly substituted starting materials are used. 5. Analogous process according to claim 1, for the production of 2-(5-amino-1H-2-benzimidazolylsulfinylmethyl)-N,N-dimethylbenzene-amln, characterized in that correspondingly substituted starting materials are used.